Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders

American Journal of Medical Genetics. Part a
Alison EatonCare4Rare Canada Consortium

Abstract

PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932). The latter has been described in multiple families presenting with complex neurologic manifestations in childhood. We describe adult siblings with biallelic PNPT1 variants identified through WES who presented with isolated severe congenital sensorineural hearing loss (SNHL). In their 40s, they each developed and then followed a nearly identical neurodegenerative course with ataxia, dystonia, and cognitive decline. Now in their 50s and 60s, all have developed the additional features of optic nerve atrophy, spasticity, and incontinence. The natural history of the condition in this family may suggest that the individuals previously reported as having isolated SNHL may be at risk of developing multisystem disease in late adulthood, and that PNPT1-related disorders may constitute a spectrum rather than distinct phenotypes.

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Citations

Jun 18, 2020·Current Rheumatology Reports·Isabelle Melki, Marie-Louise Frémond
Nov 23, 2019·Journal of Clinical Medicine·Rocio RiusJohn Christodoulou
Nov 18, 2020·Journal of Medical Genetics·Alessandra PennisiManuel Schiff
Nov 10, 2020·Movement Disorders Clinical Practice·Laurence GauquelinGrace Yoon
Sep 10, 2021·Wiley Interdisciplinary Reviews. RNA·Joanna GrochowskaRoman J Szczesny

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